Aryl mercury hydroxy mononuclear aromatic carboxylates



Patented Mar. 16, 1937 UNITED STATES ARYL MERCURY HYDROXY MONONUCLEARAROMATIC CARBOXYLATES Carl N. Andersen, Wellesley Hills, Mass., assignorto Lever Brothers Company, a corporation oi.

Maine No Drawing. Application February 4, 1936, Serial 14 Claims. (01.260-13) The present invention relates to the production of aromaticmercury salts of hydroxy substituted mononuclear aromatic acids.

It isan object of my invention to produce new organic mercury compoundsuseful as germicides and for other therapeutic purposes.

-I have discovered that when the hydrogen atom of the acidic group orgroups of hydroxy substituted mononuclear aromatic acids is replaced bythe essential radical of certain aromatic mercury compounds, compoundsare produced which have extraordinarily high potency as antiseptics andgermicides, and at the same time are characterized by relatively lowtoxicity and other desirable properties.

The compounds I have produced may be described as having the generalformula (RHg)x-R1, in which R represents an aromatic structure to acarbon atom of which the mercury is directly 20 attached; in which R1represents a hydroxy substituted mononuclear aromatic acid radical thatis linked to the RHg group or groups through the replacement of thehydrogen atom of the acidic group or groups; and in which :1: representsthe number of RHg groups attached to the acid radical. While the wordgroup is used hereinafter, it is obvious that it must be interpreted asplural when more than one RHg group is attached to the acid radical.

More particularly, R represents an aromatic structure, which may be anaromatic nucleus with or without side chains, and the expressionaromatic structure used herein is intended to be generic and include anaromatic nucleus with r or without side chains. The aromatic structureis of the type in which none of the nuclear or side chain carbon atomshas direct linkage with any element other than hydrogen, carbon ormercury. B may stand for the phenyl group, Cal-I5, or for an aromatichydrocarbon having a nucleus similar to the phenyl hydrocarbons, as, forexample, mono or polycyclic hydrocarbons in which all of the nuclearcarbon atoms, other than the one attached to mercury, and any side chaincarbon atoms, have their valences satisfied either by carbon orhydrogen. Examples are the diphenyl, tolyl, xylyl and naphthyl groups.

The radical R1 represents a radical corresponding to a mononucleararomatic compound which 50 contains one or more acidic groups, and inwhich one or more of the hydrogens attached to nuclear carbon atoms havebeen substituted by a hydroxy group. The mononuclear compound may be aderivative of benzene and its homologues, for ex- 5 ample toluene andxylene. More than one hydroxy group may be substituted in a compound andmore than one of the hydrogens of the ring may be replaced by one ormore hydroxy group and some other atom or group, for example, anymonovalent radical.

The following examples illustrate the types of acids and acidderivatives falling within the above defined class, and from whichorganic mercury salts of the type heretofore defined may be prepared;salicylic acid, p hydroxy benzoic acid, m-hydroxy benzoic acid,protocatechuic acid gallic acid, b-resorcylic acid, ,syringic acid,cresotinic acids, 3-hydroxy o-phthalic acid anhydride, 3,4- dihydroxyphthalic acid anhydride, hydroxy trimesic acid, and hydroxy mesitylinicacid.

In the case of the anhydride and other acid derivatives, the reaction isslightly difierent, as will be pointed out in more detail hereinafter.

The compounds I have prepared, together with others I have investigated,comprise a sufficiently representative number of the hydroxy substitutedmononuclear aromatic acids to lead me to believe that all of the acidsof thisgeneral group may be employed to produce my novel mercurycompounds. The compounds so prepared have in greater or lesser degree,but always in a relatively high degree, antiseptic and germicideproperties. I, therefore, regard my invention generic to and includingthe entire group of hydroxy substituted mononuclear aromatic acids ofthe above defined type.

The general method of producing these compounds consists in reactingtogether a hydroxy substituted mononuclear aromatic acid and a compoundcontaining an aromatic mercury radical of the above defined type. Acommon solvent for both reacting components is employed. The compoundresulting from the reaction is usually relatively insoluble as comparedwith the reacting components, and upon its precipitation may befiltered, washed and dried. In my application Serial No. 694,198, filedOctober 18, 1933, I have disclosed a. general method of preparingaromatic mercury compounds of this type by reacting the acidic compoundwith an aromatic mercury hydroxide. This reaction is one ofneutralization of an acid and a base to form a salt and water. This hasthe advantage that water is the only other product produced and theresulting compound may be easily purified. In my application Serial No.694,199, filed October 18, 1933, I have disclosed another general methodof preparing aromatic mercury compounds of this type by employing asoluble aromatic mercury salt, for example, the acetate or the lactate,in a reaction with the acidic compound. The aromatic mercury compoundsproduced are of a relatively low solubility as compared with thearomatic mercury salts and are relatively insoluble as compared with theacidic compound. In my application Serial No. 50,001 filed November 15,1935, I have disclosed a method of preparing aromatic mercury compoundsby reacting an acid derivative, such as an ester or anhydride with anaromatic mercury hydroxide to form the corresponding aromatic mercurysalt. Any of these general methods may be employed in producingcompounds comprising this invention.

The following examples are given as illustrative of a method by whichall of the compounds comprising this invention may be prepared and asillustrative of representative organic mercury derivatives fallingwithin the scope of my invention:

Example 1 2.94 grams of phenylmercury hydroxide is dissolved in 1 literof water. The solution is filtered to remove any gum or insolublematerial. To the filtrate is added 1.51 grams of salicylic aciddissolved in cc. of water, and the mixture is allowed to cool and standuntil precipitation is complete. The precipitate is separated byfiltration, washed thoroughly and then dried. The resulting product is awhite crystalline substance sparingly soluble in water, melting at158163 C., and is the compound phenylmercury salicylate.

Example 2 17.64 grams of phenylmercury hydroxide is dissolved in 4liters of water and heated until solution is complete. The solution isfiltered to remove any insoluble material. To the filtrate is added 8.28grams of p-hydroxy benzoic acid. A precipitate results and the mixtureis allowed to cool after which the precipitate is separated byfiltration, washed well with warm water and dried. The material has amelting point of 199 C., and. is the compound phenylmercury p-hydroxybenzoate.

Example 3 88.8 grams of p-diphenylmercury hydroxide is dissolved orsuspended in 4 liters of alcohol. To this solution is added 33.12 gramsof salicylic acid dissolved in 100 cc. of alcohol. A granularprecipitate results immediately which is separated by filtration, washedwith alcohol and dried. A further amount of the material may beseparated by cooling the mother liquor. The material sinters at C. andmelts at 191 C. with efiervescence, and is the compoundp-diphenylmercury salicylate.

Example 4 17.64 grams of phenylmercury hydroxide is dissolved in 4liters of water and heated until solution is complete. The solution isfiltered to remove any insoluble material. To the filtrate is added10.16 grams of b-resorcylic acid dissolved in 300 cc. of water. A whiteprecipitate results and the mixture is allowed to cool after which it isfiltered. The precipitate is washed well with warm water and allowed todry. It has a melting point of 154-155 C., and is the compoundphenylmercury b-rescorcylate.

Example 6 17.64 phenylmercury hydroxide is dissolved in 4 liters ofwater and heated until the solution is complete. The solution isfiltered to remove any insoluble material. To the filtrate is added anaqueous solution containing 12.4 grams of gallic acid. A greenish yellowprecipitate results and the mixture is allowed to stand in the dark. Theprecipitate is separated by filtration, washed well with warm water anddried. Upon further heating of the material, the green color increasesand the material decomposes. It is the compound phenylmercury gallate.

From the description in the above examples, it will be readily apparentto one skilled in the art how other members of the above defined group,for example, the polybasic acids, may be reacted with an aromaticmercury compound to produce the other mercury compounds which are withinthe scope of my invention.

The reacting materials are employed in substantially theoreticalquantities. In some cases, if desired, approximately 10% excess of theacid or acid derivative may be employed in order to insure a completeconversion of the aromatic mercury compound.

Any suitable solvent in which the reacting components are soluble may beused as the medium for carrying out the reaction. If they are bothsoluble in water this is generally used for reasons of convenience, butif not, other solvents such as the alcohols or acetone or mixtures ofthese with each other or with water, may be employed.

The process may be carried out at any temperature, for example, roomtemperature. In most cases I find, however, that the use of heatfacilitates the solution of the reaction components and speeds thereaction.

The compounds produced as above described are characterized byextraordinarily high potency as antiseptics and germicides. Tests todetermine the eificacy of some of them in killing B. typhosus and Staph.aureus were carried out under the following conditions:

Aqueous solutions of varying dilutions from 1:10.000 upward untilkilling ceased, were made up.

These dilutions were employed in the conduct of the tests by thefollowing methods:

Circular 198, U. S. Dept. of Agriculture, Dec. 1931, described as F. D.A method against Eberthella typhi (typhoid bacillus) at 37 C. and F. D.A. special method against Staph. aureus at 37 C.

As illustrative of the potency of the compounds, the killing power ofthe following compounds is given merely for illustration.

The figures represent the maximum dilutions at which killing in 15minutes resulted:

Staph.

B. tuphosus gum Phenylmercury salicylate 1:70, 000 1:30, 000Phenylmercury p-hydroxy benzoate 1:50, 000 1:40, 000 Phenylmercuryo-cres0tinate l: 000 1:40, 000 Phenylmercury protocatechuete.. 1:40, 000

cannot be employed. They may be used externally and locally on humanbeings and higher animals and in some cases administered internally withsatisfactory results from the germicidal standpoint and without harmfuleffect to the body or its functions. The salicylate, for example, ischaracterized by its penetration and killing power even in the presenceof extraneous organic matter. It may be injected intravenously andperitoneally with highly satisfactory results.

The compounds retain their germicidal activity when incorporated in soapand various menstrums employed in preparing germicidal compositions.

When these new compounds are to be used directly as germicides they maybe employed in aqueous or other solutions or they may be formed intovarious preparations such as mouth washes, tooth pastes, soaps,-ointments, etc.

This application is a continuation in part of my copending applicationSerial No. 694,207, filed October 18, 1933.

I claim:

1. A new organic mercury compound having the general formula (RHg)x-R1,in which R represents an aromatic structure to a carbon atom of whichthe mercury is directly attached, and in which none of the carbon atomshas direct linkage with any element other than hydrogen, carbon andmercury; in which R1 represents a hydroxy substituted mononucleararomatic acid radical, which is linked to the RHg group through thereplacement of acidic hydrogen; and in which :1: represents the numberof RHg groups attached to the acid radical, and is an integerrepresentating the number of acidic hydrogens in the acid.

2. A new organic mercury compound having the general formula RHg'R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached, and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;and in which R1 represents a hydroxy substituted mononuclear monobasicaromatic acid radical, which is linked to the RHg group through thereplacement of the acidic hydrogen atom.

3. A new organic mercury compound having the general formula RHg-Ri, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached, and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;and in which R1 represents a hydroxy substituted benzoic acid radical,which is linked to the RHg group through the replacement of the acidichydrogen atom.

4. A new organic mercury compound having the general formula RHg-R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached, and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;and in which R1 represents a monohydroxy substituted benzoic acidradical, which is linked to the RI-Ig group through the replacement ofthe acidic hydrogen atom.

5. A new organic mercury compound having the general formula RHg-R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached, and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;and in which R1 represents a polyhydroxy substituted benzoic acidradical, which is linked to the RI-Ig group through the replacement ofthe acidic hydrogen atom.

6. A new organic mercury compound having the general formula RHg-R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached, and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;and in which R1 represents a salicylic acid radical that is linked tothe RHg group through the replacement of the acidic hydrogen atom.

7. A new organic mercury compound having the general formula(CsH5Hg)X-R1, in which R1 represents a hydroxy substituted mononucleararomatic acid radical which is linked to the CsH5Hg group through thereplacement of acidic hydrogen; and in which 9: represents the number ofCsHsI-Ig groups attached to the acid radical, and is an integerrepresenting the number of acidic hydrogens in the acid.

8. A new organic mercury compound having the general formulaCsH5I-Ig-R1, in which R1 represents a hydroxy substituted mononuclearmonobasic aromatic acid radical, which is linked to the CsHsHg groupthrough the replacement of the acidic hydrogen atom.

9. A new organic mercury compound having the general formulaCs-I-I5Hg-R1, in which R1 represents a hydroxy substituted benzoic acidradical, which is linked to the CeHsHg group through the replacement ofthe acidic hydrogen atom.

10. A new organic mercury compound having the general formula CsH5Hg-R1,in which R1 represents a monohydroxy substituted benzoic acid radical,which is linked to the C'sHsHg group through the replacement of theacidic hydrogen atom.

11. A new organic mercury compound having the general formula CeH5Hg-R1,in which R1 represents a polyhydroxy substituted benzoic acid radical,which is linked to the CeHsHg group through the replacement of theacidic hydrogen atom.

12. Phenylmercury salicylate.

13. Phenylmercury gallate.

14. Phenylmercury protocatechuate.

CARL N. ANDERSEN.

